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Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Tuesday, September 21, 2010

Morphines'

Table of Contents:

1) Morphine

2) Heroin

3) Desomorphine

4) Dipropanoylmorphine

5) Dihydromorphine

6) Azidomorphine
7) Chemistry (Image)

Morphine

Basics:

Morphine is the prototype narcotic. A naturally occuring opiate and the gold standard against which all other opioids are measured. Morphine sets the medical standard for all narcotics in regards to potency, pharmacology, and subjective effects. Morphine has a history of use spanning over 200 years since its discovery in 1804. It was the first isolated alkaloid ever to be extracted from a natural source. It is the primary component of opium extracted from within the seed pod walls of the opium poppy, known by the botanical name Papaver Somniferum. Morphine may constitute anywhere from 10 to 20 percent the weight of opium, depending on climate, location, plant variety, and harvest time.

Use:

Morphine is a strong opioid analgesic and is the world's most commonly used narcotic for the relief of moderate to severe pain, acute or chronic. The drug is available in various forms to suit various therapeutic needs.

In the United States, morphine is available as its sulfate salt, i.e. morphine sulfate - in liquid, tablet, and capsule form for oral use, parenteral solutions for injection or infusion, and rectal suppositories for anal use. Also available are preservative free solutions for use by the intraspinal route. Injectable morphine solutions are available in single or multiple dose vials, with a morphine concentration ranging from 2.5mg/ml to 20mg/ml or more. The higher concentrations are often diluted with saline for single doses in opioid tolerant individuals, or in preparation of large volume parenterals (i.e. infusion via PCA, TIVA machine, regular drip, etc).

When treating pain in a hospital setting such as the emergency department, morphine is typically the first drug of choice for analgesia; most often given as a solution which is injected by intravenous, intramuscular, or subcutaneous routes. Intravenous morphine takes effect within seconds and provides full analgesia in minutes.

Morphine has become the analgesic of choice for epidural and intrathecal use in general anaesthesia and procedural analgesia. Recently, intraspinal morphine has caught on along with fentanyl and hydromrphone, in the use of spinal or subcutaneous implantable pumps. Implantable infusion pumps are often used in palliative or hospice care, or treatment of resistant pain in opioid tolerant individuals or those who experience significant side effects with oral opioids.

The tablet and capsule forms of morphine are commonly used for treatment of pain by prescription, and available in doses of 10 to 30 mg IR tablets, or doses of 15 to 200 mg as a sustained release product indicated for around-the-clock treatment of chronic pain. The long acting form is available in 12 or 24 hour tablet or capsules, the latter includes a newer product called "Embeda", which contains an opioid antagonist to deter sinful use and "abuse".

Pharmacology & Chemistry:

Morphine relieves pain by acting on the central nervous system; binding and activating opioid receptors in the brain and spinal cord - though morphine like other narcotics, activates receptor site throughout the peripheral nervous system as well, especially within the bowels & GI tract where it works to inhibit gastrointestinal motility thus reducing bowel movements. Morphine therefore is an effective treatment for diarrhea and other diseases of the bowel (i.e. poop pipes). Most of morphine's efficacy in a clinical context is mediated via the mu (micro) opioid receptors; in addition, the compound binds to delta and kappa opioid receptors. Relative to other opioids, morphine's pharmacological properties are non-selective in regards to its target receptor sites - therefore, along with the drug's intended clinical effects will be a wide range of side effects, mediated via delta or kappa activity, many of which are clinically irrellevant. These side effects may or may not be desireable to the user or patient.

Effects:

Despite remaining the standard first line opioid in treating chronic cancer & non cancer pain, morphine's non-selective pharmacology and relatively unrefined profile of effects are known to come off as 'rough' or 'dirty' to some users. Morphine's more significant side effects include dry skin, pruritis and itching which may be intense with certain individuals, constipation, nausea, and sedation or somnolence. Those receiving the drug intravenously note an often overwhelming sensation of itching, described as 'pins and needles' which is caused by the large release of histamine experienced upon a rapid introduction of morphine to the bloodstream. It is not uncommon for some users to scratch themselves senseless causing bleeding and scabbing. This effect however may be avoided with the use of an over the counter antihistamine up to 30 minutes or an hour before dosing.

None the less, the full spectrum of narcotic effects offered by morphine is highly desired and sought out by users. The euphoric & dreamy subjective effects as well as the side effects of morphine long ago set the precedent for the overall "narcotic experience" - sure enough, the natural painkillers and antidepressants produced naturally within the human body aquired their name (endorphin, endomorphin, etc) from morphine itself.

For those who experience inadequate relief or intolerable side effects with morphine; the most common second choice analgesics are typically oxycodone, hydromorphone, or fentanyl - all of which are available in regular or long acting formulations.

Heroin

Basic:

Known by the trade name Diamorphine and the common name Heroin. Diamorphine was first discovered and produced in 1874 by an English chemist while studying the combination of morphine with various acids. In 1895, the drug was produced and marketed by a German Pharmaceutical company, which is presently Bayer, the pharmaceutical giant. Bayer marketed heroin as a substitute for morphine with a lesser potential for addiction and dependence. It was later discovered that heroin in fact had no less addiction & dependency potential than its relative morphine, and that diamorphine in fact was converted to morphine once entering the brain. Research would come to show that heroin, essentially an acetylated ester of morphine, was a highly lipid (fat) soluble derivative of morphine - allowing more rapid and complete penetration of the blood-brain barrier. Heroin was essentially, a faster acting form of morphine, which simply produced a superior "rush" when injected.

Diamorphine sale and use was completely prohibited in 1914 within the United States; after which time a majority other nations followed suit, owing to US influence and the newly enacted international treaties (League of Nations, Single Convention on Narcotic Drugs).

Illicit opium for the heroin market is cultivated heavily throughout southwest asian countries of the middle east, including pakistan, and afghanistan. Most of the middle eastern supply is consumed by the european market, in both base form and salt form. Other major illicit opium sources (for the world heroin market) include southeast asia (primarily the golden triangle), colombia, turkey, and mexico.

Much of the world's diamorphine for pharmaceutical use is produced from Turkish, Tasmanian or Indian opium.

Diamorphine in liquid injectable form
(Top) Used as an analgesic in Europe.

Use:

Diamorphine is the world's most widely used illicit opioid, and is available in most countries on the illicit market in the form of a base (#3 heroin), a soluble powder (#4 heroin), or a crude form ranging from gooey and sticky to solid known as black tar heroin.

Most of the available black market heroin in the US is either a water soluble heroin hydrochloride powder, or black tar heroin - the latter of which is more common in the southwest states, smuggled via the mexican border.

Heroin is available in pharmaceutical form, generally in liquid solution for injection under the name diamorphine, or in a water soluble powder for oral/intranasal compounds or parenteral preparation.

Although pure heroin hydrochloride is a clean white powder, most street heroin varies in color. No. 4 Heroin of decent quality typically appears as a fine powder ranging in color from an off white beige to an off white pale grey. It is similar in consistency to a talc powder, and generally appears flaky when pressed tightly in a "stamp" bag, crumbling into a fine pile when removed from the package.

While diluting agents each have their own taste, relatively pure heroin has a very bitter, chemical taste which lingers in the mouth - it is similar to that of opiate based pharmaceuticals, but much stronger. If you like many others, suck the residue off the stamp bags, the strong taste may trigger nausea when combined with the emetic effect of the heroin you've administered. The taste is not unpleasant, just very strong.

Pure heroin has no significant odor, but most street heroin will have a distinct odor, often ranging from somewhat of a yeast-like scent, to a vinegar-type scent; this scent may vary depending on the type and quantity of dilutants used.

Good heroin will readily dissolve upon contact with water, and does not require "cooking". Stirring the mixture is advised, to ensure the product is fully dissolved.

Aside from the diluting & cutting agents, the vast majority of even raw, uncut heroin will have a portion of impurities from the manufacturing process. Impurities found in illicit heroin are generally limited to 6-acetylmorphine, 6-acetylcodeine, and often some traces of morphine and codeine. Morphine or 6-acetylmorphine occur due to incomplete or partial acetylation of the morphine base during the process, while 6-acetylcodeine occurs as a result of acetylation of any codeine which was extracted with the initial morphine base.

Powder heroin is most commonly dissolved in water and injected intravenously or intramuscularly; IV injection offers complete bioavailability and takes effect in 8 to 10 seconds, while IM injection takes effect anywhere between 1 and 5 minutes. Powder heroin may also be smoked using indirect heat offering an immediate effect similar to IV use, or snorted intranasally, absorbing into the blood vessels of the mucous membranes and taking effect in 5 to 10 minutes at the most. Heroin in any form is very rarely taken orally, due to its negligible oral bioavailability - i.e. a vast majority of a dose is lost before reaching the blood-brain barrier, courtesy of its trip through the liver, allowing only 20 to 25% of a given dose to actually reach the central nervous system.

Due to its illegal status in most countries including the US, heroin use comes with health and lifestyle owing to the absence of regulation and quality control. Origin and purity are unknown, and product is diluted with various fillers to increase volume and multiply profit. Intravenous use of black market heroin comes with serious health risks due to the presence of insoluble fillers - many of which may be chemicals not intended for human consumption - which may cause vascular infection, hepatitis, and obstruction of tiny blood vessels in vital organs such as the heart, lungs, or brain. On the other end of the spectrum, unwitting use of an irregularly pure batch of product may lead to overdose and death - Not knowing the purity or quality of each dose makes the risk of use exponentially greater than that of a regulated, pharmaceutical-quality product.

Due the scarcity of injecting equipment in many areas, users often re-use and share dirty needles, increasing the prevalence of Hepatitis, HIV and other blood-bourne illness/infection. Proper hygeine, proper injecting technique, not to mention a basic level of pharmacological knowledge - these are essential, however largely lacking among both urban and rural drug users, unfortunately contributing further to the stereotypes and misconceptions of opioid use - primarily heroin.

Most risks and ills associated with the illicit use of heroin come not from the drug itself, but from the lifestyle of the user as well as the unregulated nature of the drug caused by prohibition itself.

Heroin is used in a number of countries under its proper trade name Diamorphine. The drug is clinically interchangeable with morphine as an analgesic and anaesthetic, and provides remarkable relief from moderate to severe pain in the injured or terminally ill. Its relatively potent and rapid acting properties provide it advantages over morphine in certain settings. Diamorphine is used in the treatment of severe pain in a trauma or ER setting, postoperative units, intensive care units, and commonly in hospice medicine to relieve pain in cancer or other terminally ill patients, allowing a transcendent peace and pain free existence throughout one's final days, weeks, etc. Diamorphine in medicine is administered by parenteral, spinal, oral, rectal and intranasal routes.

Diamorphine in some Nations may be prescribed by physicians for the clinical maintenance of narcotic dependence to chronic addicts who have found limited success with other methods of opioid replacement such as methadone, morphine, hydromorphone, or buprenorphine. A similar approach is the establishment of supervised injecting centers - these centers serve as a safe area for the use of the drug, and often provide clean needles and injecting supplies. Some of these centers distribute pharmaceutical heroin and are staffed by a physician and medical staff. Clinical observations have shown heroin maintenance programs to be effective in maintaining the health of the addict, as well as encouraging compliance both with clinical guidelines and the law. Diamorphine as an addiction maintenance tool is prescribed either by itself or alongside a longer acting agent such as methadone. Heroin maintenance treatment and supervised heroin centers are becoming commonplace throughout Europe and Canada, and are becoming implemented or approved by multiple governments - highlighting the success of such systems.

Properties:

Heroin itself produces little effect. Diamorphine serves as a prodrug for the distribution of several metabolites; morphine, 6-acetylmorphine, and morphine-6-glucuronide. The acetyl groups of diamorphine serve the purpose of increasing the lipid solubility of the drug, allowing rapid entrance to the brain upon injection. Heroin itself contributes to only the first few seconds to minutes of effect; it is rapidly deacetylated in the bloodstream via plasma enzymes within to form 6-acetylmorphine, and eventually morphine itself further down the line. Morphine is further conjugated to form morphine-6-glucuronide, a potent mu agonist. These metabolites more easily bind to mu receptors than does heroin itself, as they all have a free 3-hydroxyl group (large factor in opioid recognition). All produce typical opioid effects via binding primarily at mu-opioid receptors centrally throughout the brain and spinal cord & peripherally within the GI tract (i.e. the gut). As with all mu agonists, they indirectly elevate mesolimbic dopamine release via binding at sites in the ventral tegmental area (VTA).

6-acetylmorphine as well as morphine-6-glucuronide, have shown affinity at the third subset of mu-receptor (mu3) which morphine itself does not activate. Affinity for this novel mu receptor is speculated to contribute to reports of heroin's distinguished subjective effects. Diamorphine when injected intravenously is approximately twice as potent as morphine by the same route as an analgesic.

Heroin may be administered orally and is done so medically in the UK. Its bioavailability by this route is highly variable, being dependent on tolerance-level of the user and highly dose dependent. In opioid naiive users taking heroin acutely, its eventual systemic morphine bioavailability is roughly 25%. In opioid dependent or regular narcotic users however, oral bioavailability of these larger doses may increase to 60-70%. In the former (opioid naiive) population, oral heroin is roughly equipotent to oxycodone via the same route. In the latter (tolerant) population, its oral potency is closer to that of PO hydromorphone.

Effects:

The effects of heroin are segmental (i.e. come in phases). Upon initial IV administration comes an immediate rush of warmth & euphoria - with pure heroin this is due to diamorphine itself, and with illicit heroin may be partially due to minor amounts of unreacted morphine or 6-acetylmorphine present as impurities in the product.

Within a minute or so of the initial rush, an intensely pleasant state of relaxation becomes present, accompanied by positive mood and euphoria. This takes place during the and after the rapid breakdown to 6-acetylmorphine, which is responsible for the majority of heroin's acute effects. Peak levels of 6-AM are typically reached within 2 minutes. This acute period is generally known as the "flash".

This is followed by further breakdown to morphine, and morphine's further breakdown into morphine-6-glucuronide. The life of each metabolite may be considered a phase of its own, however following the rush, subjective effects are nearly impossible to differentiate. The metabolic process takes place generally during the first half hour following administration. The entire course of the experience following the initial rush and conversion to 6-AM, is known as the "bang" phase, These terms being an analogy to a thunderstorm - the initial lightning flash, and the following bang of thunder.

The effects of diamorphine are similar to morphine, but with an especially pleasant initial "rush" upon injection felt throughout the body. Physiological effects may include pruritis and itching, a general flushing or warmth, pinpoint pupils (miosis), myoclonus, constipation, emesis, respiratory depression and peripheral vasodilation.

Subjective effects include analgesia physical relaxation and release of all tension, a highly euphoric sense of peaceful well being, positive mood, empathy towards others and increased sociability or "chattiness", relief of anxiety and/or stress, temporary relief from depression, increased energy with a sense of motivation or productivity - if currently active, sedation and/or somnolence with intermittent periods of nodding the head as if falling asleep, a twilight state of shallow half-sleep - often with vivid dreams ("waking dreams") best described as a dreamlike state; this is common with all opioid users and is a highly regarded & greatly renowned state, known as "vivid dreaming", "nodding out", "opiate sleep", or "morphine dreams".

Desomorphine

Unique narcotic related to morphine - distinct from morphine & other derivatives in that it lacks a furan ring & 6-alcohol substituent.

Developed in the 1930's as an alternative to morphine & diamorphine but never widely marketed due to its short duration.

Chemical name is desoxydihydromorphine - It is therefore an immediate derivative of dihydromorphine and a simple analogue of morphine. Desomorphine is 10x as potent as morphine, about equal to oxymorphone.

Rapid onset & short duration. For clinical purposes, its potency is believed to be offset by its very short duration; however, it may be particularly useful for traumatic pain due to injury, breakthrough pain, and of course as a substitute for heroin in recreational use.

Tolerance develops quickly unless administered at its minimally effective dose, at a time interval appropriate to its duration of effect.

Withdrawal appears more rapidly than with morphine and is at least as severe, but may be shorter in duration.

Desomorphine has unfortunately become associated in Russia with the street drug Krokodil - in which case it is synthesized (or rather "cooked up") by addicts, using over the counter codeine tablets as a starting material. Krokodil is a shame to the reputation of desomorphine and all opioids; as it is a low quality mixture of product containing toxic impurities, produced by lay-addicts using household chemicals & kitchen supplies. The name krokodil is a reference to "Crocodile". In reference to the scaly, rotten, boil-ridden, reptilian skin of the users who inject the crude homemade product. Use of the product by injection often leads to amputation of one or more limbs, and eventually death not by overdose, but due to the toxic & corrosive nature of the product they are injecting. This entire phenomena is a product of Russias' draconian narcotic laws - methadone maintenance is illegal in Russia. Criminal sentencing is harsh. Pain prescriptions are difficult to obtain. Those without access to heroin have turned to krokodil as a half-ass, toxic substitute.

Dipropanoylmorphine

Semi synthetic opioid of the morphine type. Dipropanoylmorphine is a heroin analogue - specifically a 3,6 propionyl ester of morphine.

Discovered more recently than other morphine esters (in 1974) therefore its history & use dates back no longer than fentanyl.

Rarely used medicinally, if at all. 3-4x as potent as morphine due to its high lipophilicity. Longer lasting than morphine and heroin due to the presence of two propionyl groups which are broken down more slowly than the acetyl groups of heroin.

Effects are similar to heroin, and include analgesia, euphoria, sedation, itching, nausea, constipation peripheral vasodilation and respiratory depression. Its effects last 3-6 hours.

Dihydromorphine

A strong opioid analgesic. Dihydromorphine is a derivative of morphine that has been hydrogenated at the 7,8 bond. Also known as Paramorphan.

First synthesized in Germany in 1900. It is a schedule 1 controlled substance in the US and therefore its medical use is illegal. Has been used elsewhere as an analgesic for moderate to severe pain.

Acts as an agonist predominantly at the mu receptor, with a low affinity for delta & kappa receptors. Frequently used in opioid receptor binding studies. Also used as a precursor or intermediate in the synthesis of other narcotics.

Saturation of the double bond makes DHM slightly more potent than morphine and longer acting. Its oral bioavailability may be greater than morphine.

Can be taken orally, rectally, intravenously, intramuscularly or subcutaneously - just as morphine.

Azidomorphine

Azidomorphine is a potent analogue of morphine and is 50x more potent. In human studies it produced prototypic opioid effects including analgesia, respiratory depression, miosis, and supression of abstinence. Subjective effects were similar to morphine - including euphoria, anxiolysis and reward.